1. Field of the Invention
The present invention relates to certain 5-fluorouracil prodrug compositions and methods for their topical administration.
2. Description of the Prior Art
Considerable research has been conducted in an attempt to solve the problem of enhancing the delivery of topically applied drugs across the topical skin membrane.
Many drugs have been found to be useful for the treatment of various skin disease states such as psoriasis and atopic dermatitis when they are given orally, but are not effective when applied topically. However, the use of a drug in a topical manner to treat a topical disease state is desirable in that only a locally effective concentration of the drug needs to be attained in the skin. On the other hand, an oral dose develops a systemic (whole body) concentration of the drug.
Although 5-fluorouracil (5-FU) is the only widely accepted topical treatment for skin malignancies and is successful in treating superficial lesions such as actinic keratoses [Dillaha et al, Arch. Dermatol, Vol. 92, page 410 (1965)] and basal cell carcinomas [Sloan et al, Int. J. Pharm., Vol. 44, page 87 (1988)], it is ineffective in treating deeper lesions or actinic keratoses of the extremities. Therefore, a more effective and less irritating therapy is generally conceded as being desirable.
There are two general approaches to enhancing the dermal delivery of any drug. The first is by a formulation approach and the second is by a prodrug approach [Waranis et al, J. Pharm. Sci., Vol. 76, page 587 (1987)].
Prodrugs comprise derivatized or other chemical and/or physically modified forms of the drug species and are designed to more readily penetrate topical barriers. Upon transport across the topical membrane, they are converted in situ to the active form, whereupon they perform their intended biological function in the target organ. These prodrugs are also designed to resist metabolic conversions and other forms of degradation until they have crossed the barrier.
5-FU is conventionally employed in a formulation containing propylene glycol (a solubilizer) and a penetration enhancer. See U.S. Pat. Nos. 3,991,203; 4,411,893; 4,415,563; 4,714,703 and 4,853,388; and Japanese Patent No. 83-79915 [abstracted in Chem. Abs., Vol. 99:58911h (1983)]. Propylene glycol is very irritating to the skin over extended courses of treatment which can last for several weeks.
Polar, high-melting, heterocyclic drugs such as 5-FU which are relatively insoluble in lipids and in water have presented a challenge to pharmaceutical chemists for some time in their efforts to improve the topical delivery of such agents so that they can be used effectively in clinical situations. One approach to meeting this challenge has been to use N-acyloxyalkyl prodrug derivatives which are lower-melting and more lipophilic than the parent drugs. Recently, a number of examples of the application of this approach to modifying heterocyclic drugs have been described [Bodor et al, U.S. Pat. No. 4,061,753; CA 87:152278 (1977) and Sloan et al, Int. J. Pharm., Vol. 12, pages 299-313 (1982); Stella et al, U.S. Pat. No. 4,163,058; CA 91:193312 (1979); Ozaki et al, U.S. Pat. No. 4,267,326; Mollgaard et al, Int. J. Pharm., Vol. 12, pages 153-162 (1982); and Sloan et al, J. Pharm. Sci., Vol. 72, pages 372-378 (1983)].
Although no examples of prodrugs have been reported where both water and lipid solubility have been optimized in order to obtain enhanced delivery of drugs across topical membranes, there are a number of prodrugs which incorporate an amino group into the derivative and exhibit enhanced lipid solubility and dermal delivery [Sloan, U.S. Pat. No. 4,206,220; CA 93:8017 (1980); Sloan and Little, CA 96:104087 (1982); Sloan, CA 97:144855 (1982); and Bodor et al, Int. J. Pharm., Vol. 10, pages 307-321 (1982)].
Although the topical membrane or skin is a "biological membrane," it differs substantially from other membranes in that the barrier to absorption of drugs is the stratum corneum which comprises a dead, dry (5-10% H.sub.2 O), compact keratin-containing material. All other biological membranes comprise live, essentially aqueous (75-80% H.sub.2 O) material. Obviously, therefore, the considerations bearing on the transport or delivery of drug species across other biological membranes are altogether different from those bearing on the delivery of drugs across the topical skin membrane.
A high degree of lipophilicity is necessary in any prodrug designed to effectively cross the skin membrane. However, the prodrug must substantially immediately convert to the parent active drug species after transport across the stratum corneum.
It has been suggested heretofore to employ certain N-Mannich type bases as prodrugs for oral or parenteral administration. See, for example, Pitman. Med. Res. Rev., Vol. 1, No. 2, pages 189-214 (1981); Johansen et al, Arch. Pharm. Chem. Sci., Ed. 8, pages 141-151, 207-214 (1980); Johansen et al, Arch. Pharm. Chem. Sci., Ed. 10, pages 111-121 (1982); Bundgaard et al, Int. J. Pharm., Vol. 7, pages 119-127, 129-136 (1980); Bundgaard et al, J. Pharm. Sci., Vol. 69, No. 1, pages 44-47 (1980); Bundgaard et al, Acta. Pharm. Suec., Vol. 18, pages 129-134 (1981); Bundgaard et al, Int. J. Pharm., Vol. 8, pages 183-192 (1981); and Bundgaard et al, Int. J. Pharm., Vol. 9, pages 7-16 (1981). There is no suggestion in the prior art, however, as to the utilization of such N-Mannich bases as topical prodrugs.
There is disclosed in U.S. Pat. No. 4,412,994 the use of Mannich base hydroxamic acid prodrugs for topical administration to warm-blooded animals. The parent drugs from which the prodrugs are derived, however, are limited to "acyl residues of non-steroidal anti-inflammatory agents containing a carboxylic acid function."
The use of Mannich bases or aminomethyl derivatives for topical delivery involves the intact prodrug partitioning from a non-protic solvent (in which it is stable) into the skin (in which it is not stable because of the presence of water) where it reverts to the parent compound. On the other hand, the use of Mannich bases or aminomethyl derivatives for oral or parenteral use take advantage of increased water solubility and increased dissolution properties of the derivatives to enhance the bio-availability of the parent drug, but it is the parent drug and not the prodrug that is actually involved in the partitioning from the aqueous environment (in which the prodrug is not stable) into the membranes and from there ultimately the systemic circulation. Thus, the topical delivery depends on the superior partitioning properties of the intact prodrug while the oral or parenteral delivery still depends on partitioning properties of the parent drug and gains its only advantage from the more immediate and higher solution concentrations of the parent drug that develop from the use of the prodrugs.
Sloan (U.S. Pat. No. 4,845,081) describes certain aminomethyl derivatives of 5-FU as well as other biologically active organic compounds which function successfully as topically applied prodrugs having an enhanced delivery or transport across the topical membrane.
It is an object of the present invention to provide novel 5-fluorouracil prodrug compositions and methods for their topical administration.